Contraindications to Trimethoprim for Uncomplicated UTI
Trimethoprim is absolutely contraindicated in patients with known hypersensitivity to trimethoprim or sulfonamides, documented megaloblastic anemia due to folate deficiency, history of drug-induced immune thrombocytopenia with trimethoprim/sulfonamides, pregnancy (especially last trimester), nursing mothers, infants under 2 months of age, marked hepatic damage, and severe renal insufficiency when renal function cannot be monitored. 1
Absolute Contraindications (FDA-Mandated)
The following are formal contraindications from the FDA drug label that must be respected 1:
- Hypersensitivity reactions: Any known hypersensitivity to trimethoprim or sulfonamides absolutely prohibits use 1
- Drug-induced immune thrombocytopenia: Any history of thrombocytopenia caused by trimethoprim or sulfonamides 1
- Folate deficiency: Documented megaloblastic anemia due to folate deficiency 1
- Pregnancy and lactation: Contraindicated in pregnant patients (sulfonamides cross the placenta) and nursing mothers (excreted in breast milk, may cause kernicterus) 1
- Age restriction: Pediatric patients less than 2 months of age 1
- Hepatic impairment: Marked hepatic damage 1
- Renal impairment: Severe renal insufficiency when renal function status cannot be monitored 1
Pregnancy-Specific Restrictions
The European Association of Urology specifically recommends avoiding trimethoprim-sulfamethoxazole in the last trimester of pregnancy due to risk of kernicterus in the newborn. 2 This aligns with the FDA contraindication for all trimesters 1, though the third trimester carries the highest risk.
Clinical Situations Requiring Alternative Antibiotics
Beyond absolute contraindications, trimethoprim should be avoided in specific clinical scenarios:
- High local resistance: Do not use empirically when local E. coli resistance exceeds 20%, as clinical cure rates plummet from 90-100% (susceptible organisms) to only 41-54% (resistant organisms) 2
- Recent trimethoprim exposure: Patients who used trimethoprim-sulfamethoxazole in the preceding 3-6 months have independently predicted resistance and should receive alternative therapy 2
- Recent international travel: Travel outside the United States within 3-6 months increases risk of resistant uropathogens 2
- Concurrent renin-angiotensin system blockers with spironolactone: While not an absolute contraindication, this combination results in 18 additional cases of hyperkalemia per 1000 UTIs treated compared to amoxicillin, representing a clinically significant risk 3
Important Safety Considerations
Trimethoprim carries increased risk of acute kidney injury (adjusted OR 1.72) and hyperkalemia (adjusted OR 2.27) compared to amoxicillin in patients over 65 years old. 3 For every 1000 UTIs treated in elderly patients, trimethoprim causes 1-2 additional cases of hyperkalemia and 2 additional hospital admissions for acute kidney injury compared to amoxicillin 3.
High-Risk Populations Requiring Caution
- Elderly patients on renin-angiotensin system blockers: Baseline risk of hyperkalemia and acute kidney injury is substantially elevated, though trimethoprim is not absolutely contraindicated unless combined with potassium-sparing diuretics 3
- Patients with renal impairment: Severe renal insufficiency is an absolute contraindication when monitoring is unavailable; lesser degrees of impairment require dose adjustment and close monitoring 1
Common Pitfalls to Avoid
- Prescribing without local susceptibility data: Hospital antibiograms overestimate community resistance; use outpatient surveillance data when available 2
- Using 3-day regimen in men: Men require 7 days of therapy, not the 3-day course used in women 2
- Ignoring resistance risk factors: Recent antibiotic use and international travel are independent predictors of treatment failure 2